The vast majority of sensory nerves in the respiratory system are bronchopulmonary C-fibers. These nerves are distributed throughout the bronchopulmonary system. Activation of these nerves can lead to sensation of irritation and reflexes including nonproductive cough, increases in mucus secretion, vasodilatation, and bronchospasm. They are typically quiet in a healthy lung, but can be activated by noxious stimuli and processes associated with airway inflammation including decreases in pH and the presence of various inflammatory mediators. They are thus designed as part of an airway defense system, but when the inflammation becomes chronic, their excessive activation likely contributes to the symptoms and pathophysiology of airway disease. The relevance of bronchopulmonary C-fibers in health and disease notwithstanding, there is a large gap in our knowledge base regarding C-fiber phenotypes in the lungs, their precise distribution, and the mechanisms of their activation. In the present proposal experiments are outlined that are aimed at providing more detailed information on the distinct phenotypes of bronchopulmonary C-fibers. We will provide new insights into the C-fiber distribution within the lungs. In addition our studies will add new knowledge regarding the biophysical mechanisms by which neurotrophins, inflammatory mediators, and protons lead to changes in electrical excitability and action potential discharge at nerve terminals within the lungs. To accomplish our aims we will bring to bear a combination of anatomical and various electrophysiological techniques that allow us to address our hypotheses in a state-of-the-art fashion.